This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Several rigorous, standardized psychiatric diagnoses studies conclude that vulnerability to a major depressive disorder (MDD) is increased at the time of the menopause transition. About 75% of perimenopausal women reported mood and sleep disorders and these disorders are likely to recur at menopause in women with bipolar illness (Parry, 2008). Estrogen replacement therapy resulted in significant (more than 80%) anti-depressive effects in pre-, perimenopausal women but has no effects in late post-menopausal women. The mechanism of the functional, structural or mechanistic alterations of estrogen response during menopausal transition remains unclear and elucidating the nature of the loss of response to exogenous estrogen in late post-menopausal women forms the objective of this proposal. We and other groups have recently identified several estrogen receptor (ER) splice variants including the dominant negative ERbeta variant, ERbeta2 in rat hippocampus. Further more, our pilot data demonstrated an increase of ERbeta2 expression in hippocampus of rats ovariectomized (OVX) more than 21 days, but not in those OVX for 5 days or non OVX. Coincident with increase of ERbeta2 expression in hippocampus of 21 days OVX rats is the loss of estrogen-induced neurogenesis which currently believe is a neural basis for antidepressants. Therefore, we hypothesize that menopausal related ERbeta2 expression may serve as a biomarker and perhaps also as a functional switch for the menopause-related loss of estrogen antidepressive effects. Three specific AIMs are designed to validate our hypothesis. 1) CHARACTERIZE THE OVARIECTOMY-INDUCED ER[unreadable]2 ISOFORM EXPRESSION IN BRAINS OF RATS AND RHESUS MONKEYS. 2) DETERMINE THE IMPACT OF ER[unreadable]2 ON E2-REGULATED BRAIN ANTI-DEPRESSIVE EFFECTS IN OVX RAT AND NON-HUMAN PRIMATE BRAIN. 3) DETERMINE THE IMPACT OF ERB2 ON E2-REGULATED BEHAVIORAL ANTI-DEPRESSIVE EFFECTS IN OVX RATS.